Discovering interactions in polypharmacy: Impact of metamizole on the metabolism of quetiapine.

AIMS: Metamizole is quite an old drug with analgesic, antipyretic and spasmolytic properties. Recent findings have shown that it may induce several cytochrome P450 (CYP) enzymes, especially CYP3A4 and CYP2B6. The clinical relevance of these properties is uncertain. We aimed to unravel potential pharmacokinetic interactions between metamizole and the CYP3A4 substrate quetiapine. METHODS: Plasma concentrations of quetiapine from a large therapeutic drug monitoring database were analysed. Two groups of 33 patients, either receiving quetiapine as a monotherapy (without CYP modulating comedications) or with concomitantly applied metamizole, were compared addressing a potential impact of metamizole on the metabolism of quetiapine being reflected in differences of plasma concentrations of quetiapine and dose-adjusted plasma concentrations. RESULTS: Patients comedicated with metamizole showed >50% lower plasma concentrations of quetiapine (median 45.2 ng/mL, Q1 = 15.5; Q3 = 90.5 vs. 92.0 ng/mL, Q1 = 52.3; Q3 = 203.8, P = .003). The dose-adjusted plasma concentrations were 69% lower in the comedication group (P = .001). Subgroup analyses did not suggest a dose dependency of the metamizole effect or an influence of quetiapine formulation (immediate vs. extended release). Finally, the comedication group exhibited a significantly higher proportion of patients whose quetiapine concentrations were below the therapeutic reference range (78.8% in the metamizole group vs. 54.4% in the control group, P = .037) indicating therapeutically insufficient drug concentrations. CONCLUSION: The combination of metamizole and quetiapine leads to significantly lower drug concentrations of quetiapine, probably via an induction of CYP3A4. Clinicians must consider the risk of adverse drug reactions, especially treatment failure under quetiapine when adding metamizole.

Outcomes of electroconvulsive therapy in patients with depressive symptoms with versus without comorbid personality disorders/traits: A systematic review and meta-analysis.

AIMS: To assess electroconvulsive therapy (ECT) outcomes in patients affected by depressive symptoms with versus without additional comorbid personality disorders/traits. METHODS: We identified observational studies investigating ECT clinical outcomes in patients affected by depressive symptoms with versus without comorbid personality disorders/traits in Embase/Medline in 11/2022. Our protocol was registered with PROSPERO (CRD42023390833). Study quality was evaluated using the Newcastle-Ottawa-Scale. Our primary outcomes were ECT response and remission rates. Meta-regression analyses included effects of in/outpatient percentages, age, number of ECT sessions, and electrode placement; subgroup analyses included the assessment methods for personality disorders/traits. We performed sensitivity analyses after excluding poor-quality studies. RESULTS: A total of 20 studies (n = 11,390) were included in our analysis. Patients with comorbid personality disorders/traits had lower remission rates (OR = 0.42, 95% CI = 0.31, 0.58, p < 0.001) with substantial heterogeneity (I2 = 93.0%) as well as lower response rates (OR = 0.35, 95% CI = 0.24, 0.51, n = 5129, p < 0.001) with substantial heterogeneity (I2 = 93.0%) compared with patients without comorbid personality disorders/traits. Relapse rates were higher in patients with versus without comorbid personality disorders/traits (OR = 3.23, 95% CI = 1.40, 7.45, k = 4, n = 239, p = 0.006) with moderate heterogeneity (I2 = 75.0%) and post-ECT memory impairment was more frequent in patients with versus without comorbid personality disorders/traits (OR = 1.41, 95% CI = 1.36, 1.46, k = 4, n = 471, p < 0.001) with minimal heterogeneity (I2 = 0.0%). Dropout rates were higher in patients with versus without comorbid personality disorders/traits (OR = 1.58, 95% CI = 1.13, 2.21, k = 3, n = 6145, p = 0.008). CONCLUSIONS: Patients with comorbid personality disorders/traits treated with ECT are reported to have lower response and remission rates and higher rates of side effects and relapse rates compared with patients without personality disorders/traits.

A Systematic Review of Clozapine Concentration-Dose Ratio from Therapeutic Drug Monitoring Studies in Children and Adolescents Treated with Clozapine for Mental Disorders.

BACKGROUND: Therapeutic drug monitoring of clozapine in children and adolescents has received insufficient attention. Calculation of concentration-to-dose (C/D) ratios from trough steady-state concentrations estimate drug clearance. METHODS: A systematic electronic literature search was conducted in 3 article databases from inception until January 10, 2023, and articles reporting clozapine concentrations in children and adolescents were retrieved. The pharmacokinetic quality of the studies was assessed, and clozapine C/D ratios were calculated using the sample mean clozapine dose and concentration. RESULTS: Of the 37 articles of potential interest, only 7 reported clozapine trough and steady-state concentrations. After excluding case reports and a study confounded by fluvoxamine, 4 studies on psychosis from Europe and the United States were included. The clozapine C/D ratios were similar to published adult values and ranged from 0.82 to 1.24 with a weighted mean of 1.08 ng/mL per mg/d. The weighted means were 334 mg/d for the dose and 380 ng/mL for the concentration. The stratified analysis of the weighted mean clozapine C/D ratios from 2 studies showed lower values in 52 male (1.05 ng/mL per mg/d) than in 46 female (1.46 ng/mL per mg/d) children and adolescents, with values similar to those reported for European adult nonsmokers. Two female adolescents had high clozapine C/D ratios (2.54 ng/mL per mg/d), an Asian American patient with borderline obesity and a patient with intellectual disability with low dosage (mean = 102 mg/d) and concentration (mean = 55 ng/mL). CONCLUSIONS: Reports on clozapine therapeutic drug monitoring in children and adolescents are limited in number and quality. Future studies should focus on basic pharmacokinetic issues, such as stratification by sex, smoking, and relevant comedications with inductive or inhibitory properties.

Assessing Pharmacokinetic Correlates of Escitalopram-Related Adverse Drug Reactions.

BACKGROUND: To assess the pharmacokinetic correlates of reported adverse drug reactions (ADRs) under antidepressant treatment with escitalopram (ESC) using a large therapeutic drug monitoring database. METHODS: A large naturalistic sample of inpatients and outpatients prescribed ESC was analyzed. ADRs were classified using the Udvalg for Kliniske Undersogelser side effect rating scale. We compared ESC-treated patients with (n = 35) and without ADRs (n = 273) using ESC plasma concentrations as the primary outcome. We also compared ADR rates in the 2 groups based on 2 cut-off ESC levels reflecting the recommended upper thresholds of the therapeutic reference range of 80 ng/mL, suggested by the consensus therapeutic drug monitoring guidelines, and 40 ng/mL, based on recent meta-analysis data. The effects of age, sex, smoking, daily ESC dose, plasma concentrations, and concentrations corrected for daily dose were included in a binary logistic regression model to predict ADRs. RESULTS: No differences in clinical, demographic, or pharmacokinetic parameters were observed between patients with and without ADRs ( P > 0.05). Patients with ESC-related ADRs were more frequently diagnosed with psychotic disorders than those without (25% vs. 7.1%, P = 0.004). None of the variables was associated with ADR risk. Overall, ADR rates were not significantly different in patients above versus below thresholds of ESC concentrations (ESC concentrations >40 [n = 59] vs. ≤40 ng/mL [n = 249] and >80 [n = 8] vs. ≤80 ng/mL [n = 300]; P = 0.56 and P = 1.0, respectively). CONCLUSIONS: No distinct pharmacokinetic patterns underlying ESC-associated ADRs were observed. Further studies with more specific assessments of ADRs in larger cohorts are required to better identify potential underlying patterns.

Behind the Curtain: Therapeutic Drug Monitoring of Psychotropic Drugs from a Laboratory Analytical Perspective.

PURPOSE: Therapeutic drug monitoring (TDM) is a well-established tool for guiding psychopharmacotherapy and improving patient care. Despite their established roles in the prescription of psychotropic drugs, the "behind the curtain" processes of TDM requests are invariably obscure to clinicians, and literature addressing this topic is scarce. METHODS: In the present narrative review, we provide a comprehensive overview of the various steps, starting from requesting TDM to interpreting TDM findings, in routine clinical practice. Our goal was to improve clinicians' insights into the numerous factors that may explain the variations in TDM findings due to methodological issues. RESULTS: We discussed challenges throughout the TDM process, starting from the analyte and its major variation forms, through sampling procedures and pre-analytical conditions, time of blood sampling, sample matrices, and collection tubes, to analytical methods, their advantages and shortcomings, and the applied quality procedures. Additionally, we critically reviewed the current and future advances in the TDM of psychotropic drugs. CONCLUSIONS: The "behind the curtain" processes enabling TDM involve a multidisciplinary team, which faces numerous challenges in clinical routine. A better understanding of these processes will allow clinicians to join the efforts for achieving higher-quality TDM findings, which will in turn improve treatment effectiveness and safety outcomes of psychotropic agents.

The boon and bane of nitrous oxide.

Nitrous oxide (N2O) has been known since the end of the eighteenth century. Today, N2O plays a huge role as a greenhouse gas and an ozone-depleting stratospheric molecule. The main sources of anthropogenic N2O emissions are agriculture, fuel combustion, wastewater treatment, and various industrial processes. By contrast, the contribution of medical N2O to the greenhouse effect appears to be small. The recreational and medical uses of N2O gradually diverged over time. N2O has analgesic and anesthetic effects, making it widely used in modern dentistry and surgery. New research has also begun studying N2O's antidepressant actions. N-methyl-D-aspartate (NMDA) antagonism and opioid effects are believed to be the main underlying biochemical mechanisms. At this point, numerous questions remain open and, in particular, the conduct of larger clinical trials will be essential to confirm N2O's use as a rapid-acting antidepressant. The N2O concentration delivered, the duration of a single inhalation, as well as the number of inhalations ultimately required, deserve to be better understood. Finally, the non-medical use of N2O has gained significant attention in recent years. Sudden deaths directly attributed to N2O are primarily due to asphyxia. Heavy, chronic N2O use may result in vitamin B12 deficiency, which, among other things, may cause megaloblastic anemia, venous thrombosis, myeloneuropathy, and skin pigmentation. Helpful biochemical tests include homocysteine and methylmalonic acid. The centerpiece of treatment is complete cessation of N2O use together with parenteral administration of vitamin B12.

Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

PURPOSE/BACKGROUND: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. METHODS: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. FINDINGS/RESULTS: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. IMPLICATIONS/CONCLUSIONS: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

Postpartum hemorrhage and postpartum depression: A systematic review and meta-analysis of observational studies.

OBJECTIVE: To assess the postpartum depression (PPD) risk in women with postpartum hemorrhage (PPH) and moderators. METHODS: We identified observational studies of PPD rates in women with versus without PPH in Embase/Medline/PsychInfo/Cinhail in 09/2022. Study quality was evaluated using the Newcastle-Ottawa-Scale. Our primary outcome was the odds ratio (OR, 95% confidence intervals [95%CI]) of PPD in women with versus without PPH. Meta-regression analyses included the effects of age, body mass index, marital status, education, history of depression/anxiety, preeclampsia, antenatal anemia and C-section; subgroup analyses were based on PPH and PPD assessment methods, samples with versus without history of depression/anxiety, from low-/middle- versus high-income countries. We performed sensitivity analyses after excluding poor-quality studies, cross-sectional studies and sequentially each study. RESULTS: One, five and three studies were rated as good-, fair- and poor-quality respectively. In nine studies (k = 10 cohorts, n = 934,432), women with PPH were at increased PPD risk compared to women without PPH (OR = 1.28, 95% CI = 1.13 to 1.44, p < 0.001), with substantial heterogeneity (I2 = 98.9%). Higher PPH-related PPD ORs were estimated in samples with versus without history of depression/anxiety or antidepressant exposure (OR = 1.37, 95%CI = 1.18 to 1.60, k = 6, n = 55,212, versus 1.06, 95%CI = 1.04 to 1.09, k = 3, n = 879,220, p < 0.001) and in cohorts from low-/middle- versus high-income countries (OR = 1.49, 95%CI = 1.37 to 1.61, k = 4, n = 9197, versus 1.13, 95%CI = 1.04 to 1.23, k = 6, n = 925,235, p < 0.001). After excluding low-quality studies the PPD OR dropped (1.14, 95%CI = 1.02 to 1.29, k = 6, n = 929,671, p = 0.02). CONCLUSIONS: Women with PPH had increased PPD risk amplified by history of depression/anxiety, whereas more data from low-/middle-income countries are required.

Effects of Sleeve Gastrectomy and Roux-en-Y Gastric Bypass on Escitalopram Pharmacokinetics: A Cohort Study.

BACKGROUND: Changes in the gastrointestinal physiology after bariatric surgery may affect the pharmacokinetics of medications. Data on the impact of different surgical techniques on the pharmacokinetics of commonly prescribed antidepressants such as escitalopram are limited. METHODS: This case-only prospective study investigated escitalopram-treated patients who underwent bariatric surgery at hospitals in Central Norway. Escitalopram concentrations were assessed using serial blood samples obtained during a dose interval of 24 hours preoperatively and at 1, 6, and 12 months, postoperatively. The primary outcomes were changes in the area under the time-concentration curve (AUC 0-24 ) with secondary outcomes, including full pharmacokinetic profiling. We performed repeated-measures analysis of variance for the AUC 0-24 and secondary outcomes. RESULTS: Escitalopram-treated obese patients who underwent sleeve gastrectomy (n = 5) and Roux-en-Y gastric bypass (n = 4) were included. Compared with preoperative baseline, dose-adjusted AUC 0-24 values were within ±20% at all time points, postoperatively in the sleeve gastrectomy and oux-en-Y gastric bypass groups, with the largest changes occurring 1 month postoperatively (+14.5 and +17.2%, respectively). No statistically significant changes in any pharmacokinetic variables over time were reported; however, there was a trend toward increased maximum concentrations after surgery ( P = 0.069). CONCLUSIONS: Our findings suggest that bariatric surgery has no systematic effect on the pharmacokinetics of escitalopram. However, because of the substantial interindividual variation, therapeutic drug monitoring can be considered to guide postoperative dose adjustments.

Changes in Psychotropic Drug Blood Levels After SARS-CoV-2 Vaccination: A Two-Center Cohort Study.

BACKGROUND: Limited evidence from case reports suggests that coronavirus disease 2019 (COVID-19) vaccination may interact with the treatment outcomes of psychiatric medications. Apart from clozapine, reports on the effect of COVID-19 vaccination on other psychotropic agents are scarce. This study aimed to investigate the impact of COVID-19 vaccination on the plasma levels of different psychotropic drugs using therapeutic drug monitoring. METHODS: Plasma levels of psychotropic agents, including agomelatine, amisulpride, amitriptyline, escitalopram, fluoxetine, lamotrigine, mirtazapine, olanzapine, quetiapine, sertraline, trazodone, and venlafaxine, from inpatients with a broad spectrum of psychiatric diseases receiving COVID-19 vaccinations were collected at 2 medical centers between 08/2021 and 02/2022 under steady-state conditions before and after vaccination. Postvaccination changes were estimated as a percentage of baseline. RESULTS: Data from 16 patients who received COVID-19 vaccination were included. The largest changes in plasma levels were reported for quetiapine (+101.2%) and trazodone (-38.5%) in 1 and 3 patients, respectively, 1 day postvaccination compared with baseline levels. One week postvaccination, the plasma levels of fluoxetine (active moiety) and escitalopram increased by 31% and 24.9%, respectively. CONCLUSIONS: This study provides the first evidence of major changes in the plasma levels of escitalopram, fluoxetine, trazodone, and quetiapine after COVID-19 vaccination. When planning COVID-19 vaccination for patients treated with these medications, clinicians should monitor rapid changes in bioavailability and consider short-term dose adjustments to ensure safety.

Clozapine once- versus multiple-daily dosing: a two-center cross-sectional study, systematic review and meta-analysis.

Evidence regarding effectiveness and safety of clozapine once- vs. multiple-daily dosing is limited. We compared demographic and clinical parameters between patients with once- vs. multiple-daily dosing in the Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (AGATE dataset), and the Department of Psychiatry, Lausanne University Hospital, Switzerland, using non-parametric tests. Effectiveness and safety outcomes were available in the AGATE dataset. We performed a systematic review in PubMed/Embase until February 2022, meta-analyzing studies comparing clozapine once- vs. multiple-daily-dosing. We estimated a pooled odds ratio for adverse drug-induced reactions (ADRs) and meta-analyzed differences regarding clinical symptom severity, age, percentage males, smokers, clozapine dose, and co-medications between patients receiving once- vs. multiple-daily dosing. Study quality was assessed using the Newcastle-Ottawa-Scale. Of 1494 and 174 patients included in AGATE and Lausanne datasets, clozapine was prescribed multiple-daily in 74.8% and 67.8%, respectively. In the AGATE cohort, no differences were reported for the clinical symptoms severity or ADR rate (p > 0.05). Meta-analyzing eight cohorts with a total of 2810 clozapine-treated individuals, we found more severe clinical symptoms (p = 0.036), increased ADR risk (p = 0.01), higher clozapine doses (p < 0.001), more frequent co-medication with other antipsychotics (p < 0.001), benzodiazepines (p < 0.001), anticholinergics (p = 0.039), and laxatives (p < 0.001) in patients on multiple- vs. once-daily dosing. Of six studies, five were rated as good, and one as poor quality. Patients responding less well to clozapine may be prescribed higher doses multiple-daily, also treated with polypharmacy, potentially underlying worse safety outcomes. Patient preferences and adherence should be considered during regimen selection.

[Psychopharmacotherapy during pregnancy and breastfeeding-Part II: focus on breastfeeding : Support options by using therapeutic drug monitoring]. / Psychopharmakotherapie in der Schwangerschaft und Stillzeit ­ Teil II: Schwerpunkt Stillzeit : Möglichkeiten der Unterstützung durch therapeutisches Drug-Monitoring.

The drug treatment of mental disorders during lactation requires special knowledge about the possible effects on the breastfed infant. The first part of this 2­part article is devoted to the use of psychotropic drugs during pregnancy. This second part addresses the use of psychotropic drugs during breastfeeding.The uncertainty about whether maternal breastfeeding can be recommended during drug treatment is high and the clinical management of psychopharmacotherapy during breastfeeding is a major challenge. Due to sparse scientific evidence, the administration of psychotropic drugs must be evaluated individually; however, the risk of mental decompensation of the mother is a weighty factor that can have a very negative impact on the mother-child pair, in the worst case up to suicide or infanticide. Drug treatment during breastfeeding is always off-label and should therefore only be given after a careful risk assessment and comprehensive clarification. Every treatment decision is a case by case decision based on an assessment of the overall constellation. This includes the psychiatric history, the current complaints and a risk assessment for the infant, ideally with the involvement of a social support network in the environment. A multiprofessional support by psychiatrists, pediatricians, gynecologists and midwives should accompany drug treatment during breastfeeding under close monitoring.This second part of the 2­part article provides an overview of the most frequently used drug classes during the breastfeeding period. Therapeutic drug monitoring (TDM) is a valuable tool for risk and exposure assessment during the breastfeeding period.

[Psychopharmacotherapy during pregnancy and breastfeeding-Part I: focus on pregnancy : Support options by using therapeutic drug monitoring]. / Psychopharmakotherapie in Schwangerschaft und Stillzeit ­ Teil I: Schwerpunkt Schwangerschaft : Möglichkeiten der Unterstützung durch therapeutisches Drug-Monitoring.

The medicinal treatment of mental disorders during pregnancy and lactation requires special knowledge about possible effects of the psychopharmacotherapy on the intrauterine exposure of the embryo/fetus. Therefore, the first part of this 2­part article focuses on the use of psychotropic drugs during pregnancy. In the second part, the use of psychotropic drugs during breastfeeding is addressed. Possible substance-specific risks as a consequence of the administration have to be assessed compared to the natural risk of pregnancy complications, birth complications and neonatal complications associated with the appropriate (untreated) mental disease. Pharmacokinetic changes during pregnancy require a special focus on the safety of drug treatment and treatment efficacy. Currently, neither the European Medicines Agency (EMA) nor the U. S. Food and Drug Administration (FDA) has approved any psychotropic drug for use during pregnancy or breastfeeding. A more detailed consideration of the risk profiles of all psychotropic drugs, prescribed off-label during this time, is important. Antidepressants, antipsychotics, and mood stabilizers are the main drugs used, despite their lack of approval. This first part of our 2­part article provides an overview of the most frequently used substance groups during pregnancy and their special characteristics. Therapeutic drug monitoring (TDM) is presented as a clinical tool that can provide a supportive contribution to treatment safety and effectiveness during pregnancy and later also during breastfeeding, not only because of the changing pharmacokinetics. In this context, the measurement of concentrations of the active substance allows a better quantification of the intrauterine and postpartum exposure risk. Despite all clinical support possibilities, each therapeutic decision for the administration of a psychotropic drug remains an individual case decision. For those involved in the treatment, this means a careful balancing of the possible consequences of non-treatment and the possible sequelae of the use of psychopharmacotherapy.

Switching antipsychotics to partial dopamine D2-agonists in individuals affected by schizophrenia: a narrative review.

OBJECTIVE: The aim of this review is to analyse the literature regarding studies centred on the clinical outcome of individuals affected by schizophrenia and treated with various antipsychotics, and then switched to orally administered partial D2-dopamine agonists (PD2A): Aripiprazole (ARI), brexpiprazole (BREX) or cariprazine (CARI). METHOD: A PubMed literature search was performed on 16 February 2021, and updated on Jan 26, 2022 for literature on antipsychotic switching in individuals affected by schizophrenia. Literature was included from 2002 onward. Six strategies were defined: Abrupt, gradual and cross-taper switch, and 3 hybrid strategies. The primary outcome was all-cause discontinuation rate per switch strategy per goal medication. RESULTS: In 10 reports on switching to ARI, 21 studies with different strategies were described, but there were only 4 reports and 5 strategies on switching to BREX. Only one study about CARI was included, but it was not designed as a switch study. The studies are difficult to compare due to differences in methodology, previous antipsychotic medication, doses of the introduced P2DA and study duration. CONCLUSION: This analysis did not reveal evidence for a preferable switching strategy. A protocol should be developed which defines optimal duration, instruments to be used, and the timing of the exams.KEY MESSAGESMost switch studies on partial D2-agonists focus on ARI, with only a few on BREX, while little is known about the clinical outcome of switching individuals to CARIThere is a wide variation of possible switch methods: Abrupt switch - gradual switch - cross-tapering switch - hybrid strategies including plateau switchThe protocols used differ considerably between the studies. A strict comparison between the studies is difficult, for which reason the present evidence does not support an unambiguous preference for a particular switch strategy.From a methodological point of view, a standardised clinical protocol should be developed to allow comparisons between studies regarding the clinical outcome of individuals switched from one antipsychotic drug to another.

Risk factors of postpartum depression and depressive symptoms: umbrella review of current evidence from systematic reviews and meta-analyses of observational studies.

BACKGROUND: Evidence on risk factors for postpartum depression (PPD) are fragmented and inconsistent. AIMS: To assess the strength and credibility of evidence on risk factors of PPD, ranking them based on the umbrella review methodology. METHOD: Databases were searched until 1 December 2020, for systematic reviews and meta-analyses of observational studies. Two reviewers assessed quality, credibility of associations according to umbrella review criteria (URC) and evidence certainty according to Grading of Recommendations-Assessment-Development-Evaluations criteria. RESULTS: Including 185 observational studies (n = 3 272 093) from 11 systematic reviews, the association between premenstrual syndrome and PPD was the strongest (highly suggestive: odds ratio 2.20, 95%CI 1.81-2.68), followed by violent experiences (highly suggestive: odds ratio (OR) = 2.07, 95%CI 1.70-2.50) and unintended pregnancy (highly suggestive: OR=1.53, 95%CI 1.35-1.75). Following URC, the association was suggestive for Caesarean section (OR = 1.29, 95%CI 1.17-1.43), gestational diabetes (OR = 1.60, 95%CI 1.25-2.06) and 5-HTTPRL polymorphism (OR = 0.70, 95%CI 0.57-0.86); and weak for preterm delivery (OR = 2.12, 95%CI 1.43-3.14), anaemia during pregnancy (OR = 1.47, 95%CI 1.17-1.84), vitamin D deficiency (OR = 3.67, 95%CI 1.72-7.85) and postpartum anaemia (OR = 1.75, 95%CI 1.18-2.60). No significant associations were found for medically assisted conception and intra-labour epidural analgesia. No association was rated as 'convincing evidence'. According to GRADE, the certainty of the evidence was low for Caesarean section, preterm delivery, 5-HTTLPR polymorphism and anaemia during pregnancy, and 'very low' for remaining factors. CONCLUSIONS: The most robust risk factors of PDD were premenstrual syndrome, violent experiences and unintended pregnancy. These results should be integrated in clinical algorithms to assess the risk of PPD.

Prevalence of impaired kidney function in patients with long-term lithium treatment: A systematic review and meta-analysis.

OBJECTIVES: Although lithium renal effects have been extensively investigated, prevalence rates of chronic kidney disease (CKD) in lithium-treated patients vary. Our aim was to provide prevalence estimates and related moderators. METHODS: We performed a systematic review in PubMed/Embase until November 01, 2021, conducting a random effects meta-analysis of studies evaluating CKD prevalence rates in lithium-treated patients calculating overall prevalence ±95% confidence intervals (CIs). Meta-regression analyses included sex, age, body mass index, smoking, hypertension, diabetes, cardiovascular disease, lithium-treatment dose, duration, and blood levels. Subgroup analyses included sample size, diagnoses, and study design. Pooled odds ratios (OR) were estimated for studies including patients receiving nonlithium treatment. Study quality was assessed using the Newcastle-Ottawa scale. RESULTS: Five, nine, and six trials were rated as high, fair, and low quality, respectively. In 20 studies (n = 25,907 patients), we estimated an overall prevalence of 25.5% (95% CI = 19.8-32.2) of impaired kidney function; despite lack of differences (p = 0.18), prevalence rates were higher in elderly samples than mixed samples of elderly and nonelderly (35.6%, 95% CI = 21.4-52.9, k = 2, n = 3,161 vs. 25.1%, 95% CI = 19.1-31.3, k = 18, n = 22,746). Prevalence rates were associated with longer lithium treatment duration (p = 0.04). Cross-sectional studies provided lower rates than retrospective studies (14.5%, 95% CI = 13.5-15.5, k = 6, n = 4,758 vs. 29.5%, 95% CI = 22.1-38.0, k = 12, n = 17,988, p < 0.001). Compared with 722,529 patients receiving nonlithium treatment, the OR of impaired kidney function in 14,187 lithium-treated patients was 2.09 (95% CI = 1.24-3.51, k = 8, p = 0.005). CONCLUSIONS: One-fourth of patients receiving long-term lithium may develop impaired kidney function, although research suffers from substantial heterogeneity between studies. This risk may be twofold higher compared with nonlithium treatment and may increase for a longer lithium treatment duration.

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Antenatal Antidepressant Prescription Associated With Reduced Fetal Femur Length but Not Estimated Fetal Weight: A Retrospective Ultrasonographic Study.

PURPOSE/BACKGROUND: Antidepressants are among the most frequently prescribed medications during pregnancy and may affect fetal weight. Associations between antenatal antidepressant use and ultrasonographic measures of fetal development have rarely been examined. We hypothesized that the prescription of an antenatal antidepressant would be associated with lower estimated fetal weight (EFW). METHODS/PROCEDURES: A retrospective analysis of routine ultrasonographic data extracted from electronic medical records was performed on a cohort of pregnant women with psychiatric diagnoses and grouped according to the presence of an antenatal antidepressant prescription (n = 32 antidepressant-prescribed and n = 44 antidepressant prescription-free). After stratifying for gestational age, comparisons included 13 ultrasonographic parameters, frequency of oligohydramnios and polyhydramnios and growth deceleration, and maternal serum protein markers assessed per routine care, including α-fetoprotein, free ß-human chorionic gonadotropin, and unconjugated estriol levels, using t tests, nonparametric and Fisher tests, and effect sizes (ESs) were computed. FINDINGS/RESULTS: No statistically significant EFW differences between groups at any time point were detected (P > 0.05). Antenatal antidepressant prescription was associated with lower femur length at weeks 33 to 40 (P = 0.046, ES = 0.75) and greater left ventricular diameter at weeks 25 to 32 (P = 0.04, ES = 1.18). No differences for frequency of oligohydramnios or polyhydramnios or growth deceleration were observed (P > 0.05). We did not detect group differences for maternal proteins (P > 0.05). IMPLICATIONS/CONCLUSIONS: Our evidence suggested a lack of association between antenatal antidepressant prescription and lower EFW but indicated an association with lower femur length and greater left ventricular diameter in mid-late gestation. Future research should examine the clinical implications of these findings.

European Whites May Need Lower Minimum Therapeutic Clozapine Doses Than Those Customarily Proposed.

PURPOSE/BACKGROUND: A nomogram from a British naturalistic study proposed that the clozapine dosing needed to reach a serum concentration of 350 ng/mL ranged from 265 mg/d (female nonsmokers) to 525 mg/d (male smokers). Some European reviews have used these dosing recommendations, which seem greater than what we found in an Italian White sample ranging from 245 mg/d (female nonsmokers) to 299 mg/d (male smokers). Five other published samples of European Whites were added to the Italian sample to estimate clozapine doses recommended for reaching 350 ng/mL. METHODS/PROCEDURES: Average clozapine metabolizers were obtained by eliminating outliers with confounding variables: (1) psychiatric inducers and inhibitors; (2) doses less than 100 mg/d; and (3) when possible, patients with inflammation, obesity, or using oral contraceptives. The study included 1363 average metabolizer European Whites: the Italian sample and 5 new samples. Mean averages that reached serum concentration levels of 350 ng/mL were calculated after stratification by sex and smoking status in each sample. Then, weighted mean averages were obtained by combining the 6 samples. FINDINGS/RESULTS: The estimated weighted mean clozapine dosages ranged from 236 to 368 mg/d (236 mg/d in 218 female nonsmokers, 256 mg/d in 340 male nonsmokers, 357 mg/d in 269 female smokers, and 368 mg/d in 546 male smokers). IMPLICATIONS/CONCLUSIONS: Our recommended dosages are less than those recommended in Europe. Future studies in European Whites need to replicate these recommended doses for average metabolizer patients after sex and smoking stratification and further explore clozapine dosing for those with relevant clinical confounders.

Metamizole but not ibuprofen reduces the plasma concentration of sertraline: Implications for the concurrent treatment of pain and depression/anxiety disorders.

AIM: Comorbidity of pain and depression or anxiety is a challenging clinical phenomenon, often requiring the concurrent application of antidepressant and analgesic drugs. Growing evidence suggests that the analgesic metamizole exhibits cytochrome P450 inducing properties. In the present study, we assessed the impact of metamizole and ibuprofen on plasma concentrations of the selective serotonin reuptake inhibitor sertraline. METHODS: Out of a therapeutic drug monitoring (TDM) database, three groups of patients were compared: patients receiving sertraline and metamizole (n = 15), patients receiving sertraline and ibuprofen (n = 19), and a matched control group without one of the analgesics (n = 19). RESULTS: Metamizole was associated with 67% lower median sertraline plasma concentrations compared to the control group (14 vs 42 ng/mL, P < 0.001). In contrast, differences between the ibuprofen group and the control group did not reach statistical significance (31 vs 42 ng/mL, P = 0.128). Moreover, the metamizole group demonstrated lower dose-adjusted drug concentrations than the ibuprofen group (0.10 vs 0.26 (ng/mL)/(mg/day), P = 0.008). Finally, the metamizole group exhibited a higher proportion of patients whose sertraline concentrations were below the therapeutic reference range (40% in the metamizole group, 5% in the ibuprofen group, 0% in the control group, P = 0.005) indicating therapeutically insufficient drug concentrations. CONCLUSION: Our findings support preliminary evidence that metamizole acts as a potent inductor of cytochrome P450 isoenzymes CYP2B6 and CYP3A4. We observed a clinically meaningful pharmacokinetic interaction between metamizole and sertraline, leading to insufficiently low sertraline drug concentrations. Clinicians should therefore consider alternative drug combinations or apply TDM-guided dose adjustment of sertraline.